Long QT syndrome (LQTS) is characterized by a prolonged QT interval and an increased risk for syncope, seizures, and sudden cardiac arrest. Ventricular fibrillation (VF) stemming from congenital LQTS is a leading identifiable cause for autopsy-negative sudden unexplained death. With a prevalence of 1 in 2500 individuals, LQTS is the most common cardiac channelopathy and has become a model disease for all other cardiac channelopathies. Over the past decade, there have been substantial improvements made in the clinical management of LQTS. However, the level of breakthrough events, the suboptimal side effect profile, and the fact that none of the current therapeutic strategies directy target the pathogenic substrate of LQTS, specifically the dysregulation of cardiac ion channels, motivates the quest for novel therapeutic strategies for LQTS. The development of patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has provided a novel model system to study the pathological substrate of LQTS, as well as test novel therapeutics. With mutations in the KCNQ1-encoded Kv7.1 voltage-gated potassium channel accounting for the pathogenic substrate for the largest portion of gene positive LQTS cases, targeting these defects may hold the greatest therapeutic potential. Due to the dominant-negative characteristics of KCNQ1 mutations along with the evidence that increased levels of mutant protein lead to increased disease severity, reducing the relative amount of mutated protein should attenuate or correct the disease phenotype. Recent advances in gene therapy have underlined the developing role of RNA interference (RNAi) as a potential therapeutic option in cardiac genetic disorders. These studies have all largely used RNAi targeted against a specific pathogenic mutation. For LQTS, this severely limits the clinical utility of a RNAi-based strategy as the vast majority of pathogenic mutations are family specific. However, targeting high frequency synonymous single nucleotide polymorphisms (sSNPs) in KCNQ1, located on the mutated allele, would allow for allele-specific RNAi in a much larger population creating a much broader clinical application. To this end, we plan to develop allele- specific RNAi targeting the two most common KCNQ1 sSNPs and characterize the effect of this RNAi on the LQTS phenotype of patient-specific iPSC-CMs. By validating a SNP-based RNAi approach in LQTS, this method may also hold potential for other genetically mediated channelopathies and cardiomyopathies.